The understanding of the mechanical indentation on a curved specimen (e.g., microspheres and microfibers) is of paramount importance in the characterization of curved micro-structured materials, but there has been no reliable theoretical method to evaluate the mechanical behavior of nanoindentation on a microsphere. This article reports a computational study on the instrumented nanoindentation of elastic-plastic microsphere materials via finite element simulation. The finite element analyses indicate that all loading curves are parabolic curves and the loading curve for different materials can be calculated from one single indentation. The results demonstrate that the Oliver-Pharr formula is unsuitable for calculating the elastic modulus of nanoindentation involving cured surfaces. The surface of the test specimen of a microsphere requires prepolishing to achieve accurate results of indentation on a micro-spherical material. This study provides new insight into the establishment of nanoindentation models that can effectively be used to simulate the mechanical behavior of a microsphere.